Neural growth hormone: regional regulation by estradiol and/or sex chromosome complement in male and female mice.

Erin P Harris,Emilie F Rissman,Kayla M Quinnies,Savera RJ Shetty,Paul J Bonthuis

doi:10.1186/s13293-015-0026-x

Erin P Harris, Emilie F Rissman + Show 3 more

Open Access

https://doi.org/10.1186/s13293-015-0026-x

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Abstract

BackgroundSex differences in pituitary growth hormone (GH) are well documented and coordinate maturation and growth. GH and its receptor are also produced in the brain where they may impact cognitive function and synaptic plasticity, and estradiol produces Gh sex differences in rat hippocampus. In mice, circulating estradiol increases Gh mRNA in female but not in male medial preoptic area (mPOA); therefore, additional factors regulate sexually dimorphic Gh expression in the brain. Thus, we hypothesized that sex chromosomes interact with estradiol to promote sex differences in GH. Here, we assessed the contributions of both estradiol and sex chromosome complement on Gh mRNA levels in three large brain regions: the hippocampus, hypothalamus, and cerebellum.MethodsWe used the four core genotypes (FCG) mice, which uncouple effects of sex chromosomes and gonadal sex. The FCG model has a deletion of the sex-determining region on the Y chromosome (Sry) and transgenic insertion of Sry on an autosome. Adult FCG mice were gonadectomized and given either a blank Silastic implant or an implant containing 17β-estradiol. Significant differences in GH protein and mRNA were attributed to estradiol replacement, gonadal sex, sex chromosome complement, and their interactions, which were assessed by ANOVA and planned comparisons.ResultsEstradiol increased Gh mRNA in the cerebellum and hippocampus, regardless of sex chromosome complement or gonadal sex. In contrast, in the hypothalamus, females had higher Gh mRNA than males, and XY females had more Gh mRNA than XY males and XX females. This same pattern was observed for GH protein. Because the differences in Gh mRNA in the hypothalamus did not replicate prior studies using other mouse models and tissue from mPOA or arcuate nucleus, we examined GH protein in the arcuate, a subdivision of the hypothalamus. Like the previous reports, and in contrast to the entire hypothalamus, a sex chromosome complement effect showed that XX mice had more GH than XY in the arcuate.ConclusionsSex chromosome complement regulates GH in some but not all brain areas, and within the hypothalamus, sex chromosomes have cell-specific actions on GH. Thus, sex chromosome complement and estradiol both contribute to GH sex differences in the brain.

Highlights

Sex differences in pituitary growth hormone (GH) are well documented and coordinate maturation and growth
four core genotypes (FCG) mice that were treated with an estradiol implant at the time of gonadectomy had higher levels of mRNA in the cerebellum than those that were given a blank implant (Figure 1A; F1,49 = 8.61, P < 0.006), demonstrating for the first time that estradiol increases Gh mRNA levels in the cerebellum
Gonadal sex and sex chromosome complement modify Gh mRNA In the hypothalamus of FCG mice, there was a main effect of gonadal sex; males had less Gh expression as compared to females (Figure 1C; F1,47 = 4.41, P < 0.05)

Summary

Introduction

Sex differences in pituitary growth hormone (GH) are well documented and coordinate maturation and growth. GH and its receptor are produced in the brain where they may impact cognitive function and synaptic plasticity, and estradiol produces Gh sex differences in rat hippocampus. In mice, circulating estradiol increases Gh mRNA in female but not in male medial preoptic area (mPOA); additional factors regulate sexually dimorphic Gh expression in the brain. We assessed the contributions of both estradiol and sex chromosome complement on Gh mRNA levels in three large brain regions: the hippocampus, hypothalamus, and cerebellum. GH receptors are present throughout the brain, and animal and human studies have implicated central GH signaling in neural functions [7]. Feeding behavior has been linked to GH [13], and GH expression, in the hypothalamus is associated with sexually dimorphic body weight differences [14]

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